Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine

This post hoc subgroup analysis of a large phase 3 study compared the efficacy and safety of eribulin versus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received second-line treatment. In the phase 3 study, women with advanced/metastatic breast cancer and ≤ 3 prior chemotherapies were randomized 1:1 to eribulin mesilate 1.4 mg/m2 intravenously on days 1 and 8, or twice-daily oral capecitabine 1.25 g/m2 on days 1–14 (21-day cycles). This analysis included 392 patients. Median overall survival was longer in patients receiving eribulin compared with capecitabine (16.1 vs 13.5 months, respectively; HR 0.77, P = 0.026). Median progression-free survival and response rates were similar between arms. Both treatments had manageable safety profiles.


Introduction
The prognosis for advanced or metastatic breast cancer (MBC) remains poor, with a 5-year relative survival rate of 26% [1]. The backbone of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer includes anti-HER2 agents. However, for patients with HER2-negative tumors (~ 75% of patients with breast cancer) [2] who have progressed following first-line chemotherapy, no single optimal treatment has been established. Current guidelines recommend the use of sequential monotherapy to balance efficacy and toxicity [3][4][5]. In the secondline setting, a limited number of chemotherapeutic regimens, often administered in combinations, significantly prolonged survival [6][7][8][9]. Although single-agent capecitabine has not demonstrated a significant survival benefit after failure of chemotherapy, its safety profile makes it one of the most frequently used second-line therapies [10,11].
Eribulin mesilate is a microtubule dynamics inhibitor with a distinct mode of action that involves binding to specific sites on the growing plus ends of microtubules [12,13]. In the pivotal phase 3 trial (Study 305/EMBRACE), eribulin significantly improved overall survival (OS) compared with treatment of physician's choice [14]. Study 301, which compared eribulin and capecitabine in locally advanced or MBC, showed that eribulin failed to demonstrate a statistically significant improvement in OS [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.77-1.00; P = 0.056] [15]. However, a separate pooled analysis from Study 301 and Study 305, requested by the European Medicines Agency (EMA), which assessed treatment effect according to HER2 status, showed that eribulin improved OS in patients with HER2-negative MBC (HR 0.82; 95% CI 0.72-0.93) [16], and specifically in the second-line or later setting (HR 0.85; 95% CI 0.76-0.94) [17]. Based on the pooled analyses, the EMA extended eribulin's label to include routine use in a second-line setting [18]. Here, we present a post hoc subgroup analysis from Study 301 comparing the efficacy and

Methods
The study design, eligibility criteria, and statistical analyses have been described in full previously [15] and are summarized here:

Ethical approval
All patients provided written informed consent. Approval was obtained from independent ethics committees and regulatory authorities in participating countries. The study was conducted in accordance with the World Medical Association Declaration of Helsinki, guidelines of the International Conference for Harmonisation/Good Clinical Practice, and local ethical and legal requirements.

Patient population
The primary study enrolled female patients aged ≥ 18 years with histologically or cytologically confirmed locally advanced or MBC, who had received ≤ 3 prior chemotherapy regimens (of which no more than 2 for advanced and/or metastatic disease) and prior therapy with an anthracycline and a taxane. The present analysis included patients with HER2-negative tumors (HER2-negative/hormone receptorpositive and triple negative) treated in the second line. The co-primary endpoints were OS and progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and safety.

Statistical analysis
Subgroup analysis was performed using the same statistical approaches (statistical model, missing data handling, and censoring rules) as the primary analysis. HRs of eribulin versus capecitabine were estimated in stratified Cox regression models with region as a stratification factor. P values of treatment differences were estimated using a Cox model.
Kaplan-Meier estimates and distribution curves were determined within each arm. Safety data were summarized descriptively using data from all patients who received at least 1 dose of study treatment and had at least 1 post-baseline safety evaluation. Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events v3.0; AEs were classified using the Medical Dictionary for Regulatory Activities.

Eribulin Capecitabine
No. of patients at risk:

Discussion
Treatment options for patients with HER2-negative MBC remain limited, with guidelines recommending singleagent chemotherapy [3][4][5]. Registration of a new agent in the metastatic setting beyond the first line requires demonstration of survival benefit [19]. In Study 301, eribulin did not demonstrate a significant survival benefit compared with capecitabine. However, it did show a heterogeneous treatment effect with a more favorable OS in patients with HER2-negative disease [15,20]. Patient populations in large randomized trials such as this one are typically heterogeneous because of worldwide accrual, with a highly variable standard of care due to the range of drugs that may be licensed in each country. A pooled analysis from Study 305 and Study 301, requested by the EMA, demonstrated that eribulin increased survival rates compared with control treatment in patients with HER2-negative MBC and provided support for an extension of its label to include routine use in a secondline setting [16,17]. In this post hoc subgroup analysis of Study 301, which evaluated patients with HER2-negative MBC receiving eribulin or capecitabine as second-line treatment, prolonged OS benefit with the use of eribulin versus capecitabine was observed, supporting its activity as a second-line treatment for patients with HER2-negative MBC. Disease characteristics in both treatment groups were generally similar with the exception of a smaller percentage of patients with ≥ 3 organs involved and a larger percentage of patients with non-visceral disease in the eribulin group. Both treatments had manageable, non-overlapping, safety profiles. These findings, although exploratory, may aid in treatment decisions in the absence of prospective study data in patient populations that match the approved European Union indication for eribulin. Other factors may be considered in treatment decisions for second-line therapy, including toxicity profiles, residual effects from prior chemotherapy regimens, and modality of administration.